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Evaluation of the effect of pentoxifylline and natural honey on morphine dependence in mice
(Tabriz University of Medical Sciences, School of Pharmacy, 2025) Rabiei, Erfan; Habibi Asl, Bohlool; Najafi, Moslem
Introduction: In the process of forming dependence and tolerance to opioids, various mechanisms such as increased oxidative stress, increased activity of the glutaminergic system, etc. are observed. Pentoxifylline and natural honey are among the drugs with antioxidant properties. Aim: The purpose of this study was evaluation the effect of pentoxifylline and natural honey on morphine dependence in mice.Methods: 90 male mice in 9 groups of 10 in the weight range of 20-30 g were randomly selected and received the following medication regimens once a day for two weeks. 1-Saline (10ml/kg,ip) +Saline (10ml/kg,ip) 2-Saline (10ml/kg,ip) + Morphine (25mg/kg,ip) 3,4,5- pentoxifylline (20,40,80mg/kg,ip) + Morphine (25mg/kg,ip) 6,7,8-Natural Honey (100,200,400mg/kg,ip) + Morphine (25mg/kg,ip) 9- pentoxifylline (20mg/kg,ip) + Honey (100mg/kg,ip) + Morphine (25mg/kg,ip) On the fourteenth day, naloxone (4mg / kg, ip) was injected into animals two hours after morphine injection and withdrawal symptoms were measured within half an hour. Finally, to measure serum MDA and TAC levels in different groups, the animals were anesthetized and blood samples were taken from the heart.Results: The results showed that intraperitoneal injection of honey in 3 doses (100, 200 and 400 mg/kg) and pentoxifylline with a dose of (20, 40, 80 mg/kg) each alone causes a significant reduction in the symptoms of morphine dependence.Conclusion: The findings of our study showed that the chronic consumption of honey in a non-dose-dependent manner and pentoxifylline in a dose-dependent manner had a beneficial effect in reducing the symptoms of morphine withdrawal syndrome and this effect is probably related to the anti-inflammatory properties of flavonoids in Honey and the antioxidant effects of pentoxifylline.
Evaluation of the effect of dextromethorphan and bupropion in reversing morphine-induced tolerance in mice
(Tabriz University of Medical Sciences, School of Pharmacy, 2025) Hemmaty Pour, Sina; Habibi Asl, Bohlool; Charkhpour, Mohammad; Parvizpur, Alireza
Introduction: Changes in the function of glutamatergic, dopaminergic and adrenergic systems are among the changes that occur in chronic morphine use. Dextromethorphan is an antitussive and has inhibitory effects on NMDA receptors. Bupropion, as an antidepressant, inhibits the metabolism of dextromethorphan and increases its release into the CNS. Aim: The aim of the study was to evaluate the effect of dextromethorphan and bupropion in the treatment of morphine-induced tolerance in mice. Material & Method: several mices (11 groups, 10 in each, 20-30g) were randomly selected for the following regimens for 17 days: 1. Saline (10ml/kg, 1st-17th days, S.C.) + Saline (10ml/kg, 11th-17th days, S.C.) 2. Morphine (10mg/kg, 1st-17th days, S.C.) + Saline (10ml/kg, 11th-17th days, S.C.) 3, 4, 5. Morphine (10mg/kg, 1st-17th days, S.C.) + Dextromethorphan (15,30,60 mg/kg/12h, 11th-17th days, S.C.) 6, 7, 8. Morphine (10mg/kg, 1st-17th days, S.C.) + Bupropion (40,80,110 mg/kg/12h, 11th-17th days, S.C.) 9, 10, 11. Morphine (10mg/kg, 1st-17th days, S.C.) + Dextromethorphan (15,30,60 mg/kg/12h, 11th-17th days, S.C.) + Bupropion (110,80,40 mg/kg/12h, 11th-17th days, S.C.). once on day11 and once on day17, the hotplate test was performed by injecting a test-dose morphine (9mg/kg) to animals. Results: Injection of dextromethorphan (15mg/kg) and bupropion (80mg/kg and 110mg/kg) and co-injection of dextromethorphan (15mg/kg) and bupropion (110mg/kg) accelerated tolerance compared to S+M group. However, in the injection of bupropion (40mg/kg) and co-injection of dextromethorphan (60mg/kg) and bupropion (40mg/kg), we observed a delay in tolerance compared to S+M group. Significant changes were also observed in MDA and TAC levels in bupropion (mg/kg 40) and dextromethorphan (60mg/kg) and bupropion (40mg/kg) groups compared to S+M group. Conclusion: The co-injection of dextromethorphan (60mg/kg) and bupropion (40mg/kg) and use of bupropion (40mg/kg) seem to be suitable for delaying tolerance to morphine; further studies are needed to observe precise mechanisms.
The preventive effect of bee pollen methanolic extract on morphine-induced tolerance and dependence in male mice
(Tabriz University of Medical Sciences, School of Pharmacy, 2025) Pourreza Soltan Ahmadi, Ferdous; Habibi Asl, Bohlol; Eteraf Oskouei, Tahereh
Introduction: The treatment of chronic pain presents a considerable difficulty, particularly due to opioid dependence, which is marked by tolerance and withdrawal symptoms. The mechanisms involved in the development of morphine tolerance and dependence include increased expression of P-glycoproteins and NMDA receptors, as well as activation of the oxidative stress system. Bee pollen, with its antioxidant effects and anti-inflammatory appears to have beneficial effects in preventing morphine tolerance and dependence.Aim: To evaluate the effects of bee pollen on morphine-induced tolerance and dependence in male mice.Methods: Fifty male mice (20–30 g) were randomly divided into 5 groups and subjected to the following regimens for 10 days: Saline control group, morphine control group, and three groups receiving bee pollen (12/5, 25, 50 mg/kg). On the eleventh day, following the acquisition of base latency time from the animals, morphine (9 mg/kg, ip) was administered, and the hot plate test was conducted over one hour. One hour after the hot plate test, naloxone (4 mg/kg, ip) was injected, and withdrawal symptoms (jumping and standing) were measured over 30 minutes. Blood samples were then collected, and the serum was separated to determine for the determination of serum levels of MDA and TAC. Results: Pretreatment by bee pollen, before morphine administration, decreased the development of tolerance to the antinociceptive action of morphine and also reduced naloxone-precipitated withdrawal jumps and standing on feet.Conclusion: Bee pollen (12/5, 25, 50 mg/kg, ip) reduces prevents morphine dependence and tolerance in animals, most likely due to its beneficial mechanisms through the inhibition of the oxidative stress system.
Evaluation of the effect of chronic administration of pirfenidone on the tolerance to the analgesic effects of morphine in male mice
(Tabriz University of Medical Sciences, School of Pharmacy, 2025) Rostamzadeh, Shiva; Charkhpour, Mohammad; Parvizpour, Alireza
Introduction: The chronic use of opioids causes dependence and tolerance towards them, and various mechanisms such as oxidative stress and increased production of inflammatory factors are involved in this process; The antioxidant and anti-inflammatory effects of pirfenidone have been proven. Aim: The current study aimed to investigate the effect of chronic administration of pirfenidone on the tolerance to the analgesic effects of morphine in mice.Methods: The experiment was conducted in 6 groups of 8 mice, in first group, 8 mice were given two injections every day at interval of half an hour and each time 10 (ml/kg, i.p.) of normal saline, in second group, 10 (ml/kg) every day. kg, i.p) morphine and half an hour before that 10 (ml/kg, i.p) normal saline, in third group morphine (mg/kg, i.p 10) and half an hour before that 1 ml/kg containing pirfenidone DMSO (10%) and in other three groups, we injected three different doses of pirfenidone (25/50/100 mg/kg, i.p.) one hour before morphine. In all groups, we performed a hot plate test every other day for half an hour after the injections. Finally, blood was taken from all groups and TAC, MDA, TNF-a, IL-1, and IL-6 factors were analyzed. Results: In the group receiving vehicle and morphine on day 5 and in the groups receiving doses of 25, 50 and 100 mg/kg pirfenidone along with morphine on days 11, 11 and 3, respectively, tolerance was established, but only the dose of 25 mg/kg pirfenidone was significantly (P<0.05) delayed tolerance to morphine. Also, the level of inflammatory factor IL-6 showed a significant difference (P<0.001) only in the group receiving the pirfenidone (25 mg/kg) compared to the morphine group. Conclusion: Probably, pirfenidone (25 mg/kg) delayed the onset of tolerance to morphine due to its anti-inflammatory effects. We need more studies to understand it better.
Evaluation of the effects of Carvacrol on Morphine induced tolerance and dependence in male mice
(Tabriz University of Medical Sciences, School of Pharmacy, 2024) Kenarangi, Farzaneh; Habibi Asl, Bohlol; Khalili Fard, Javad
Introduction: The mechanisms involved in the development of morphine tolerance and dependence include increased expression of P-glycoproteins and NMDA receptors, as well as activation of the oxidative stress system. Carvacrol, with its antioxidant effects, inhibition of P-gp gene expression, and NMDA receptor inhibition, appears to have beneficial effects in preventing morphine tolerance and dependence.Aim: To evaluate the effects of carvacrol on morphine-induced tolerance and dependence in male mice.Methods: Fifty male Swiss mice (weighing 20–30 grams, n=5) were randomly divided and subjected to the following regimens for 10 days: saline control group, morphine control group, and three groups receiving carvacrol (10, 20, 40 mg/kg). On the eleventh day, following the acquisition of base latency time from the animals, morphine (9 mg/kg, ip) was administered, and the hot plate test was conducted over one hour. One hour after the hot plate test, naloxone (4 mg/kg, ip) was injected, and withdrawal symptoms (jumping and rearing) were measured over 30 minutes. Blood samples were then collected, and the serum was separated for the determination of serum levels of MDA and TAC.Results: Administration of different doses of carvacrol (10, 20, 40 mg/kg, ip) did not cause significant changes in morphine tolerance reduction. However, administration of carvacrol (20, 40 mg/kg, ip) resulted in a significant decrease (**P<0.01) in morphine-induced dependence. Carvacrol (20, 40 mg/kg, ip) significantly decreased (***p<0.001) the serum MDA level, and carvacrol (40 mg/kg, ip) significantly increased (**p<0.01) the serum TAC level compared to the morphine control group. Conclusion: Carvacrol (20, 40 mg/kg, ip) prevents morphine dependence in animals, likely due to its beneficial mechanisms through the inhibition of the oxidative stress system.
Evaluation of the effects of Thymus vulgaris essential oil in preventing morphine-induced tolerance and dependence in male mice
(Tabriz University of Medical Sciences, School of Pharmacy, 2024) Safari, Azin; Habibi Asl, Bohlol; Khalili Fard, Javad
Introduction: Previous research has demonstrated the roles of the glutamatergic system and oxidative stress in the development of morphine tolerance and dependence. Thymus vulgaris essential oil, due to its antioxidant properties and inhibitory effects on NMDA receptors, may effectively prevent morphine-induced tolerance and dependence.Aim: The aim of this study was evaluating the effects of intraperitoneal administration of Thymus vulgaris essential oil in preventing morphine-induced tolerance and dependence in male mice.Methods: Fifty male mice (20-30 grams) were randomly assigned to five groups of ten: a saline control group, a morphine control group, and three groups receiving Thymus vulgaris essential oil at doses of (25, 50, 100 mg/kg, i.p.). Treatments were administered daily for ten consecutive days. The essential oil was injected 30 minutes prior to the daily morphine injection. On day eleven, baseline measurements were taken, followed by the administration of morphine (9 mg/kg, i.p.) and the hot plate test was conducted within one hour. One hour after the hot plate test, naloxone (5 mg/kg, i.p.) was injected, and withdrawal symptoms were recorded for 30 minutes. The animals were then anesthetized, and blood samples were collected from the heart to measure serum levels of malondialdehyde (MDA) and total antioxidant capacity (TAC).Results: Administration of Thymus vulgaris essential oil at all doses (25, 50, 100 mg/kg, i.p.) significantly prevented morphine-induced tolerance and dependence (***P<0.001). The highest dose (100 mg/kg, i.p.) significantly decreased serum MDA levels (***P<0.001) and increased serum TAC levels (*P<0.05).Conclusion: The results suggest that Thymus vulgaris essential oil prevents morphine-induced tolerance and dependence, partially through its inhibitory effects on oxidative stress. Further studies are recommended to evaluate its potential in managing morphine-induced tolerance and dependence.
Evaluation of the effectes of Erythromycin and Dextromethorphan on morphine induced tolerance in mice
(Tabriz University of Medical Sciences , School of Pharmacy, 2024) Sattari shiraz, Mohammad; habibi asl, Bohlul; Charkhpor, Mohammad
Introduction:Several mechanisms (increasing NMDA receptors, increasing p-gp gene expression, etc.) are involved in the tolerance to the analgesic effects of morphine. Dextromethorphan is an antitussive and a p-gp substrate. On the other hand, erythromycin, is macrolide antibiotics, also has an inhibitory effect on p-gp.Aime: The aime of this study was to investigate the effects of dextromethorphan and erythromycin in the treatment of tolerance to the analgesic effects of morphine in mice.Matrial and Method:100 male mice in 10 groups of 10 in the weight range of 20-30 grams were randomly selected and given drug regimens of Saline (10 ml/kg, ip) or Morphine (25 mg/kg, ip) to develop tolerance to morphine once a day for fourteen days. Then on the fifteenth day, different doses of erythromycin (50, 100, 200 mg/kg, ip), or dextromethorphan (10, 20, 40 mg/kg, ip) and dextromethorphan (10 mg/kg, ip) + erythromycin (50 mg) /kg, ip) half an hour before the test injection of morphine (9 mg/kg, ip) was injected into the mice. Finally, the analgesic effects caused by the morphine (9 mg/kg, ip) were evaluated in the studied groups by the Hot plate method for one hour.Results & Conclusion: The results showed that different doses of dextromethorphan (10, 20, 40 mg/kg, ip) and erythromycin (50 mg/kg, ip) have a significant effect on returning tolerance to the analgesic effects caused by morphine.Also, in the combined injection of dextromethorphan (10 mg/kg, ip) + erythromycin (50 mg/kg, ip), a significant effect was observed in returning tolerance to analgesic effects.
Evaluation of the Effects of Cetirizine and Hydroalcoholic Extract of Green Tea on Morphine-Induced Tolerance in male mice
(Tabriz University of Medical Sciences , School of Pharmacy, 2023) Fazli, Zahra; Asnaashari, Solmaz; Habibi asl, Bohlool; Eteraf-Oskouei, Tahereh
Introduction:Chronic consumption of opioid analgesics leads to the development of tolerance to their pain-relieving effects. Some of the factors contribute to this tolerance including increased oxidative stress and upregulation of the P-gp gene expression.Cetirizine is an antihistamine that inhibits P-gp.Green tea extract possesses antioxidant and anti-inflammatory properties and also inhibits P-gp.Therefore, it seems that Cetirizine and green tea extract may be effective in mitigating tolerance.Objective:The aim of this study was to investigate the effects of Cetirizine and hydroalcoholic extract of green tea on morphine-induced analgesic tolerance in the male NMRI albino mice.Methods: Male mice(20-30 g, n=100)were randomly divided into 10 groups of 10 in each. They received Saline(10 ml/kg,ip) or Morphine(25mg/kg,ip) daily for 14days to induce morphine tolerance. On the 15th day, the different doses of Cetirizine(5-10-20mg/kg, ip) were administered in the 3-5groups,and hydroalcoholic green tea extract(50-100-200mg/kg,ip) in the 6-8, EXT (50mg/kg, ip) + Cetrizine (5mg/kg, ip) in the group 9 and DMSO 10% w/v in group 10, Cetirizine(10mg/kg,ip) in the group 11, half an hour before injecting the test dose of Morphine(9mg/kg,ip) in all groups.Results: Cetirizine(5-10-20mg/kg,ip) at 30 minutes and Cetirizine (10mg/kg,ip) at 45 and 60minutes have a significant effect on returning tolerance to the analgesic effects of morphine. While the injection of different doses of EXT(50-200 mg/kg, ip) did not show a significant effect in returning the tolerance to the analgesic effects caused by morphine. In the combined injection of two drugs EXT(50 mg/kg, ip) + Cetirizine(5mg/kg, ip) no significant effect was observed in returning tolerance to the analgesic effects of morphine.Conclusion: Different doses of Cetirizine increase the analgesic effects of morphine in morphine-tolerant animals. In order to obtain the exact mechanism, we need additional studies.
Evaluation of the effectes of atorovastatin and simvastatin on morphine induced tolerance in mice
(Tabriz University of Medical Sciences , School of Pharmacy, 2023) banimasoud, Armin; Habibi Asl, Bohloul; Najafi, Moslem; Soraya, Hamid
Introduction: Morphine is one of the most widely used opioid analgesic that is used to control severe pain. Tolerance to the analgesic effects of morphine is one of the problems caused by the chronic use of morphine. Several mechanisms (inhibition of NMDA receptors, increased p-gp gene expression, etc.) are involved in the emergence of tolerance to the analgesic effects of morphine. Atorvastatin and simvastatin are both from the family of statins and also they are P-glycoprotein inhibitors.Purpose: The purpose of this study was to investigate the effects of atorvastatin and simvastatin in reducing tolerance to the analgesic effects of morphine in mice. Methods: 80 male mice in 8 groups of 10 in the weight range of 20-30 grams were selected randomly and they received Saline (10 ml/kg, ip) or Morphine (25 mg/kg ip) to develop tolerance to morphine once a day for fourteen days. Then on the fifteenth day, different doses of atorvastatin (5-10-20 mg/kg, ip) in groups 3-5 and simvastatin (2.5-5-10 mg/kg, ip) in groups 6-8 were injected to the mice. The analgesic effects caused by morphine test dose (9mg/kg, ip) were evaluated by hot plate method.Results: The results showed that different doses of atorvastatin (5-10-20mg/kg, ip) did not have a significant effect on reversing tolerance to the analgesic effects caused by morphine. while significant effect of simvastatin (2.5mg/kg, ip) was effective in reversing the tolerance to the analgesic effects of morphine (P<0.01). Conclusion: Simvastatin has beneficial effects in dose of (2.5mg/kg, ip) in reversing tolerance to the analgesic effects of morphine.
Evaluation of the effect of risperidone and methyl prednisolone on morphine induced tolerance in mice
(Tabriz University of Medical Sciences , School of Pharmacy, 2023) ahangar, Faezeh; habibi asl, Bohloul; parvizpour, Alireza
Introduction: Chronic use of opioid painkillers causes tolerance to the analgesic effect. Increased expression of P-glycoprotein gene in blood-brain barrier causes tolerance. Risperidone inhibits P-glp. Antioxidants are effective in reducing tolerance to morphine;methyl prednisolone and risperidine are antioxidant.Aim: The aim of the present study was to evaluate the effects of chronic intraperitoneal administration of methyl prednisolone and risperidine on the incidence of morphine analgesic tolerance in male mice.Method: 81 male mice in 9 groups of 9 in the weight range of 20-30 grams were randomly selected and received drug regimens containing risperidine and methyl prednisolone once a day for two weeks. Doses of risperidine (0.01,0.02,0.04mg/kg, ip) and methyl prednisolone (10, 20, 40 mg/kg, ip) were injected every half hour before the daily injection of morphine. Then, on the 15th day, the analgesic effects of morphine dose test (9 mg/kg, ip) were evaluated by hot plate method. After conducting behavioral studies in different groups, the animals are anesthetized and blood is taken from the heart to measure the serum level of MDA and TAC.Result: The results showed a significant effect in different doses of methyl prednisolone in reducing tolerance due to morphine injection,and there were significant changes in the serum levels of MDA in 20, 40 mg/kg ,but there were no significant changes in the serum levels of TCA in any of the groups. The selected dose range of risperidone did not have any significant change in reducing tolerance and changes in serum levels.Conclusion: Different doses of methylprednisolone drug were effective in preventing tolerance, and part of this effect may be related to the antioxidant effects of the drug. Also, Risperidone was not able to prevent tolerance in this dose range and it is necessary to study other doses of this drug

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